Thiophene compounds and methods for obtaining the same



Patented Aug. 19, 1947 I I UNITED STATES PATENT OFFICE THIOPHENE COMPOUNDS AND METHODS FOR OBTAINING THE SAME Frederick F. Blicke, Ann Arbor, Mich, assignor to The Regents of the University of Michigan, Ann Arbor, Mich., a body corporate of Michigan No Drawing. Application August 6, 1945, Serial No. 609,336

13 Claims. (01. 260-293) 1 2 This invention relates to new basic thiophenic prepared by the reaction of the hydrochloride esters and methods for obtaining the same, said salt of a thiophenic acyl chloride of the formula, esters having the general formula for the free base R4 5 R;- R H on I I O Rz -COYN N-R 01 I s R8 I 10 CH cH--0H R5 I with a basic alcohol of the formula,

R7 where R represents a member of the class consisting of hydrogen and lower alkyl radicals, R1 represents a member of the class consisting of hy- R8 drogen and CH3, R2 represents F member of the whereby the desired basic thiophenic ester is obclass hydrogen, chlorine, bromine, iodine and tamed said ester having the formula lower alkyl radicals, R3, R4, R5, and Rs represent R R the same or different members of the class con- (g sisting of hydrogen and lower alkyl radicals, Y OH H represents a saturated divalent hydrocarbon resi- 1 0 I due of 2 to 6 carbon atoms, R7 and Rs represent R I N R the same or difierent members of the class con- 2 s r sisting of lower alkyl radicals and R7, R8 and N I R8 I may be taken together to form a saturated hetero- ()H- CH cyclic ring system such as pyrollidine, piperidine, morpholine and the like. 5 a

The thiophene compounds of the present inven- In the above formulas the R groups and Y have tion, because of their polyfunctional nature, are the same significance as given above. useful as intermediates for the synthesis of a num- Th reaction of the thiophenic acyl chloride ber of difierent types of organic compounds. hydrochlorides with the various basic alcohols, These new compounds are also usefu1 therapeutic R7 agents and in general they are characterized by their analgesic, antispasmodic and sedative effects both in humans and in animals. These new R basic thiophenic esters may be administered in the form of their bases or in the form of their may be Carried out in dry inert organic solvent such as benzene, toluene, xylene, petroleum ether, :55; Z 5: g ?g igg gfig fii g fig? 40 chloroform andthe like, but I prefer to carry out dflodic add Sulfuric, acid, nitric acid phosphoric this reaction usmg an excess of the base alcohol, acid, acetic acid, sulfamic acid, lactic acid, tar- R1 taric acid, gluconic acid, malic acid, maleic acid, benzoic acid, phthalic acid, salicylic acid, succinic acid, fumaric acid, and the like acids. R

The new compounds of the invention maybe as the solvent.

3 4 Some of the basic alcohols, The ester is dissolved in anhydrous ether and the solution treated with an excess of dry hy- Y OH drogen chloride. The dihydrochloride which precipitates as a slightly gummy solid i dis- Rs 5 solved in hot isobutyl alcohol and ether added used in accordance with the present invention to 0 the Solution until the Salt begins to Separate. react with the thiophenic acyl chlorides are com- The mixture is cooled and the crystalline dimercially available while the others may be prehydrochloride of the fl-dimethylaminoethyl ester pared by known methods. For example, these of 2-[4'-(1-methyl-4-carboxypiperidyl)l thiobasic alcohols may be prepared by the reaction of phene collected and dried in vacuo.

O CHIiCHz H HC] 3 N CH OH OH C N-C a. z 2 rl o1 CHaOHz H,-oH,

t! OH on, onion, I 0

2 N-omomonnol \S/C-O\ 01120113 N-CH3 CHaCHn OCHzCHzN omen;

CH;---CH:

the appropriate alkylene oxides or alkyl halo- A mixture consisting of 15 g. of the acid chlohydrins withasecondary amine. ride hydrochloride of 2-[4-(1-methyl-4-car- The thiophenic acyl chlorides hydrochlorides, boxypiperidyD] thiophene (prepared as described used as starting materials, may be prepared, for 1 in Example 1) and ml. of ,B-diethylaminoexample, as described in my copending applica" ethanol is heated on a steam bath for two hours.

tion No. 609,335, filed August 6, 1945. The excess amino alcohol is removed by distilla- The invention is illustrated by the following tion under reduced pressure and the residue examples. treated with 75 ml. of Water. The mixture is CH3 CH A mixture consisting of 15 g. of the acid chloacidified with dilute hydrochloric acid, treated ride hydrochloride of 2-[4'-(1'-methyl-4-carwith charcoal and filtered. The filtrate is made boxypiperidyDl thiophene (prepared, for exalkaline by the addition of excess 5% sodium ample, as described in Example 1 of my copendhydroxide solution, the precipitated ester exing' application No. 609,335, filed August 6, 1945), tracted with ether and the ether extracts dried and 25 ml. of ,B-dimethylaminoethanol is heated go over anhydrous magnesium sulfate. The drying on a steam bath for tWo hours. The excess agent is removed by filtration and the ether amino alcohol is removed .by distillation under distilled from the filtrate. The residue is distilled reduced pressure and the residue taken up in '75 under reduced pressure to yield the pure {3- ml. of water. The mixture is acidified with dilute diethylaminoethyl ester of 2-[4'(1'-methyl-4- hydrochloric acid, filtered and the filtrate treated (55 carboxypiperidyDl thiophene; B. P. 2l518 with charcoal. The mixture is filtered and excess C./l1 mm.

5% sodium hydroxide added to the filtrate. The 10 g, of the pure ester is dissolved in 200 ml. precipitated ester is extracted with ether, the of dry ether and the resulting solution treated ether extracts dried over anhydrous magnesium with an excess of dry hydrogen chloride. The sulfate, the ether distilled and the residue fracdihyd-rochloride salt which separates as a slighttionated under reduced pressure. The pure 5- ly gummy solid is collected, Washed with dry dimethylaminoethyl ester of 2- [4'-(l-methyl-4- ether and recrystallized twice from iso-butanolcarboxypiperidyDl thiophene is obtained as a ether mixture. After drying in vacuo for sevvery light colored oil boiling about 210 C. at eral hours the analytically pure dihydrochloride 11 mm. of mercury. salt of the fi-diethylaminoethyl ester of 2- [4 (1' methyl-4'-carboxypiperidyl) thiophene melts at 154-55 C.

The dihydrobromide salt of the ester is prepared by treating a dry ether solution or the ester with dry hydrogen bromide. The white precipitated salt is collected, Washed with dry ether and purified by recrystallization from isobutariol ether mixture.

Example 3.--,e-Pyrrolidz'noethyl ester of 2-[4- (1 '-methyZ-4-carboa:ypiperidyl) l thiophene 6 i A mixture consisting of 15 g. of the acid chlo-v ride hydrochloride of 2- [4-(1-methyl-4'-carboxypiperidyD] thiophene (prepared as described in Example 1) and 30 m1. of e-piperidinoethanol is heated on a steam bath for about two hours. The excess amino alcohol is removed by distillation under reduced pressure, the residue treated with 75 m1. of water and the mixture acidified with dilute hydrochloric acid. The solu- 10 tion is treated with charcoal, filtered and the CHzCHz N-CHa A mixture consisting of g. of the acid chloride hydrochloride of 2- [4'-(1'-methyl-4-carboxypiperidyD] thiophene and m1. of fl-pyrrolidinoethanol is heated on a steam bath for two hours. The excess amino alcohol is removed by distillation under reduced pressure, the residue treated with '75 ml. of water'and the mixture acidified with dilute hydrochloric acid. The solution is treated with charcoal, filtered and the filtrate treated with an excess of 5% sodium hydroxide solution. The ester is extracted with ether, the ether extracts dried over anhydrous magnesium sulfate, the drying agent removed by filtration and the ether distilled. The residue is fractionated under reduced pressure (about 5 mm. of mercury) to obtain the pure p-pyrrolidinoethyl ester of 2- [4'4 l-methy1-4'-carboxypiperidyl) thiophene.

5 g. of the pure ester is dissolved in 100 ml. of

anhydrous ether and the resulting solution treated with an excess of dry gaseous hydrogen iodide. The precipitated dihydroiodide salt is collected, washed with ether and recrystallized from n-propyl alcohol-ether mixture.

Example 4. s-Piperidinoethyl este'r of 2-[4'-(1'- methyl-4'carbo:typiperidyl)l thiophene OHzCHz H Hi filtrate treated with an excess of 5% sodium hydroxide solution. The precipitated ester is extracted with ether, the ether extracts dried over anhydrous magnesium sulfate and the drying agent removed by filtration. The ether is distilled from the filtrate and the residue fractionally distilled under a pressure of about 5 mm. of mercury to obtain the pure B-piperidinoethyl ester of 2- [4'-(1'-methy1-4-carboxypiperidyl) I thiophene.

10 g. of the pure ester is dissolved in 200 ml. of anhydrous ether and the resulting solution treated with a slight excess of dry hydrogen chloride. The white dihydrochloride salt which precipitates is collected, washed with ether and recrystallized from. n-proDanol-dry ether mixture.

5 g. of the pure ester is dissolved in a small amount of absolute ethanol and a solution containing an equivalent amount of maleic acid in absolute ethanol is added. The mixture is evaporated to dryness and the crude maleic acid salt of the ester purified by recrystallization from absolute ethanol-ether mixture.

7 Example a--p-Morpholmoethyl ester of 2-[4'- 1-"-methyl-4"-carboxypiperidyl)l thiophene A mixture consisting of g. of the acid chloride hydrochloride of 2-[4'-(1'-methyl-4-carboxypiperidyD] thiophene and 35 ml, ore-morpholinoethanol is heated on a steam bath for tWo hours and then the excess amino alcohol distilled oiT under reduced pressure. The dry residue is treated with '75. ml. of water, the mixture acidified with dilutehydrochloric acid, treated with charcoal: and'filtered; An excess of 5% sodium hydroxide solution is added to the filtrate and the precipitated ester extracted with ether. The ether extractsare dried over anhydrous magnesiumsulfate, the drying agent removed by filtration and the ether distilled from the filtrate. The residue is fractionally distilled under about 5 mm. pressure to obtain the desired p-morpholinoethyl ester of 2-[4'-(1-methyl-4'-carboxypiperidyDl thiophene.

10 g-.. of the pure ester is dissolved in 200 m1. of anhydrous ether and the resulting solution treated with a slight excess of dry aseous hydrogen chloride.

The White precipitated dihydrochloride salt of the fi-morpholinoethyl ester of 2-[4'-(1-methyl- 4- -carboxypiperidyl) l-thiophene is removed by filtration, Washed with dry ether and recrystallized from n-propanol-ether mixture.

Example 6.-y-Di'ethylamznopropyl ester of 2- [4 (1'-methyZ-4 carbomypiperidyl)l thiophene A mixture consisting of 15 g. of the acid chloride hydrochloride of 2-[4'-(l-methyl-4-carboxy-piperidyD] thiophene and 35 ml. of y-diethylaminopropanol is heated on a steam bath for three hours. The excess amino alcohol is distilled off under reduced pressure and the dry residue treated with ml. of water. The mixture is acidified with dilute hydrochloric acid, treated with charcoal and filtered; The clear filtrate is made alkaline in the cold With 5% sodium hydroxide solution and the free base of the ester extracted with ether. The ether extracts are dried over magnesium sulfate, filtered and the ether distilled from the filtrate. The

residualloil is distilled under diminished pressure to yieldlthe desired y-diethylaminopropyl ester of 2 [4 (1 methyl-4 -carboxypiperidyl) thiophene.

10 g. of the freshly distilled basic ester is dis- CHzCH2 I o I onion:

-co N-CH3.HCl+3 N-omomomon s C] CHaCH: oHl H,

oH,-----om omen, I l 0 2 NOHzCH CH OH.HC1 o-o 01120113 2 2 s NOHa CHaCHz V OCH2CH1CH2N Hz-CH1 Example 7. -Piperidmoprpyl ester of 2-[4'- (1 methyl 4' carborylpiperidyl) l--bromothzophene \l CH2---OH1 Hz- H2 A mixture consisting of g. of the hydrochloride salt of the acid chloride of 2-[4-(1- methyl-4-carboxypiperidyl) l-5-bromothiophene (prepared, for example, as described in Example 6 of my co-pending application No. 609,335, filed August 6, 1945) and 35 ml. of y-piperidinopropanol is heated on a steam bath for three hours. The excess amino alcohol is distilled off under reduced pressure and the dry residue treated with 100 m1. of water. The mixture is acidified with dilute hydrochloric acid, treated with charcoal and filtered. The filtrate is made alkaline in the cold with 5% sodium hydroxide solution and the ester base extracted with ether. The combined ether extracts are dried over magnesium sulfate, the drying agent removed by filtration and the ether distilled. The residue is heated under about 2 mm. pressure at 100 C. in an oil bath to remove any remaining y-piperidinopropyl, cooled and the vacuum. released. The residue consists of y-piperidinopropyl ester of 2 [4' (1 methyl-4'-.carboxypiperidyl) l-5- bromothiophene. The ester may be purified by recrystallization of the dihydrochloride salt. The residue is taken up in anhydrous ether and the resulting solution treated with a slight excess of dry hydrogen chloride. The white precipitated dihydrochloride salt is removed by filtration, washed with dry ether and recrystallized from n-propanol-dry ether mixture.

Examp le 8.5-Diethy1laminobutyl ester of 2-[4- (1 -ethyZ-4' -carb oxym'peridyl) l-5 methylthiophene CHSCHZ lief CHr-CH: N-CH:

OCHzOHzCHnN I chloride salt of the acid chloride of 2-[4'- (lethyl 4' carboxypiperidyD] 5 methylthio phene (prepared, for example, as described in' Example 8 of my co-pending application, No. 609,335, filed August 6, 1945) and 35 ml. of a-diethylaminobutanol is heated on a steam bath for three hours and then the excess amino alcohol distilled off under reduced pressure. The dry residue is treated with ml. of water, the resulting mixture acidified with dilute hydrochloric acid, charcoaled and filtered. The clear aqueous filtrate is made alkaline in the cold with 5% sodium hydroxide solution and the free base of the ester extracted with ether. The combined ether extracts are dried over magnesium sulfate, the drying agent removed by filtration and the ether distilled from the filtrate. The residue is distilled under a pressure of about 1 mm. of mercury to obtain the pure t-diethylaminobutyl ester of 2- [4 (1' ethyl 4 carboxypiperidyD] 5- methylthiophene.

10 g. of freshly distilled ester is dissolved in 200 ml. of dry ether and a slight excess of dry gaseous hydrogen iodide passed into the resulting solution. The white dihydriodide salt which separates is collected, washed with anhydrous ether and purified by recrystallization from n-propanel-dry ether mixture.

A mixture consisting of g. of the acid chloacid addition salts such as the dihydrochloride,

ride'hydrochloride of 2- [4-(1'-n-propy1-2l', 3, 5', 6' tetramethyl 4 carboxypiperidyb] 4- dihydrobromide and the like.

methyl-S-chlorothiophene hydrochloride (pre- Example 10. 5 Diethylamino h a methylbutyl ester of 2E4'-(1-2'sopropyZ-3, 5-diethyZ-4- carboacy-piperz'dyll) J-S-t-butylthiophene (EHQCHS CH CH2 CH3 0 CH3 OH CHzCH3 I l CH3-C -0 N-OH semen-omomcnm I S CH; 01 CH; CHZCH/ I H Hz C zCHa 1 01120113 oH--on1 311 OHZOHa 3113- I 0 on, 2 CHzCHCHzCHzCHzNJiCI CHa-(F s 0 /OH3 CHzCHa N-CH CHgCHa CH3 OCH(CHZ)3N Hz CHZCH;

(IJH CH: 01120113 pared, for example, as described in Example 12 of my co-pending application No. 609,335, filed August 6, 1945) and ml. of fl-di-n-butylaminoethanol is heated on a steam bath for three hours and then the excess amino alcohol removed by distillation under reduced pressure. The dry residue is treated with 100 ml. of water, the mixture acidified with dilute hydrochloric acid, charcoaled and filtered. The clear filtrate is made alkaline in the cold with 5% sodium hydroxide and the precipitated ester extracted with ether. The combined ether extracts are dried over anhydrous magnesium sulfate, the drying agent' removed by filtration and the ether distilled from the filtrate. The residue is heated at 100 C. in an oil bath under a pressure of about 1 mm. of mercury to remove any of the amino alcohol remaining in the product, cooled and the vacuum released. The residue consists of substantially pure p-di-n-butylethyl ester of 2*-[4-(l-n-propyl-2, 3', 5', 6-tetramethyl-4'-carboxypiperidyl) 1-4-methy1-5-chlorothiophene which may be purified further by recrystallization of one of its A mixture consisting of 20 g. of the hydrochloride salt of the acid chloride of 2-[4'-'(1--isopropyl-3', 5'-diethylA-carboxypiperidyl) l-5-t-butylthiophene (prepared, for example, as described in Example 13 of my co-pending application No. 609,335, filed August 6, 1945) and 35 ml. of l-diethylaminol-pentanol is heated on a steam bath for three hours and then the excess amino alcohol is distilled off under reduced pressure. The residue is taken up in ml. of water,the mixture acidified with dilute hydrochloric acid, charcoaled and filtered. The clear filtrate is made alkaline with 5% sodium hydroxide solution and the ester extracted with ether. The combined ether extracts are dried over magnesium sulfate, filtered and the ether distilled. The residue is heated at 100 C. in an oil bath under a pressure of about 0.5 to 1 mm. of pressure in order to remove any remaining amino alcohol and then cooled. The residue consists of practically pure B-diethyl-amino-a-methylbutyl ester of 2- [4- (1- iso-propyl-3', 5'-diethyl-i-carboxypiperidyl) ]-5- t-butylthiophene.

13 Ezvample z1.e-Diethylaminopentyl ester of 2- [4'-(1-n-amyZ-3'-methyZ-4'-carboa:y-5'-n-butylpipen'dyl)l-5-iodothiophene A mixture consisting of 1&5 g. of the hydrochloride of the acid chloride of 2-[4-(1-namyl-3- methyl-4-carboxy-5-n-buty1piperidyl) 5-iodothiophene (prepared, for example, as described in salt by treating the ether solution of the base with a slight excess of dry gaseous hydrogen chloride.

Example 12.--p-Methylethylaminoethyl ester of 2-[4'- (1'-methyl-4'-carbowyp peridyl) l -4,5-d'i- *methylthiophene CH2 CH2 OH3 II I 0 CH3 7 I orn o NCHQ.HCI +3 NCH2CH2OH 7 I 01 01130112 CHz-CH:

, i CH2 CH2 0 CH I14? OH CH3 sxsf' a N-CHa 2 N-omomonflol OCHzOHzN i C1130 2 CHzCHa CH2, H2

my co-pending application No. 609,335, filed Au- A mixture consisting of 20 g. of the hydrogust 6, 1945), and 30 ml. of e-diethylaminopenchloride salt of the acid chloride of 2-[4-(1- tanol-l is heated on a steam bath forlfour hours. methyl-4% carboxypiperidyl) ]-4,5- dimethylthio- The excess amino alcohol is removed by distillaphene (prepared, for example, as described in tion in vacuo and the residue treated with Example 7 of my oo-pending application No. m1. of water. The mixture is acidified with dilute 0 609,335, filed August 6, 1945), and 35 m1. of hydrochloric acid, charcoaled, filtered and the methylethylaminoethanol is heated on a steam filtrate made alkaline in the cold with 5% sodium bath for three hours. The excess amino alcohol hydroxide solution. The ester is extracted with is removed by distillation in vacuo and the dry ether, the ether extracts dried over magnesium residue treated with 100 ml. of Water. The mixsulfate and the drying agent removed by filtra- 5 ture acidified. with dilute hydrochloric acid, tion. The ether is distilled and theresidue heated treated with charcoal and filtered. The clear for a short time at 100 C. in an oil bath under filtrate is made alkaline in the cold with 5% so a pressure of about 0.5 to 1 mm. to remove any diu-m hydroxide solution and the free ester exremaining amino alcohol. The residue is cooled, tracted with ether. The combined ether extracts taken up in ether, charcoaled and the solution 7 0 arejdried-over anhydrous magnesium sulfate, filfiltered. The free base of the e-diethylaminopentyl ester of 2-H-(1'-n-amyl-3'-methy1-4'- carboxy -5'-n butylpiperidyl) ]-5- iodothiophene may be obtained by'evaporation of the ether or the ester may be isolated as its dihydrochloride -tredand" the ether distilled. The residue is distilled under reduced pressure to obtain the methyl- 4? -carboxyp iperidyl) l-4,5- dimethylthioanswer 15. Example 13.-fi-MethyZ-iso-propylaminoethyl ester of 2-[4-(1-ethyZ-3'-methyl-4'-carboxypiperzdyl) l --n-butylthiophene CHr-CHI i 0 OH:

CH3CHzCHzCHz s C\ N-CH:CHa.HCl 3 CH l Cl C I N-CHaQHzOH H H2 IGH:

CHg-CH2 CH 0 CH3 I OH CHsCHzCHaCH -C CHCHB N"'OH2CH3 S I C a N-CHaCHaOHJICl OCHzCHzN A mixture consisting of g. of the acid chloride hydrochloride of 2-[4-(1-ethyl-3-methyl14- carboxypiperidyD] 5 n butylthiophene (prepared, for example, as described in Example 11 of my co-pending application No. 609,335, filed August 6, 1945) and ml. of fl-methyl-iso-propylaminoethanol is heated on a steam bath for three hours and then the excess amino alcohol removed by distillation under reduced pressure. The residue is treated with 100 ml. of water and the mixture acidified with dilute hydrochloriclacid. ,The solution is. treated with charcoal, filteredandtthe filtrate made alkaline with 5% sodium hydroxide solution. The ester is extracted with ether, the ether extracts dried over magnesium sulfate and filtered. The ether is evaporated from the filtrate and the residue heated for a short time at 100C. in an oil bath under about l'mm. of pressure in order to remove any remaining amino 2811001101. The residue consists of the desired ,B-methyliso-propylaminoethyl ester of "2-[4'-(1-ethyl- 3- methyl-4'- carboxypiperidyl) l-5- n-butylthiophene. The product may be vpurified iurtherif desired by distillation under reduced pressure or by recrystallization-of its dihydrochloride salt.

What I claim is:

1. Compounds of the class consisting of ;a free base and its acid addition salts, saidfree base having the formula,

where R represents a member of-the classconsisting of hydrogen and loweralkyl radicals, R1

and Rs represent members of the class consisting Y,

of hydrogen and lower .alkyl radicals, Y represents a saturated divalent hydrocarbon radicalof 2 to 6 carbon atoms, R7 and Rs represent members of the class consisting of lower alkyl radicals independently bonded to the N and lower alkylene where R represents a member of the class consisting of 'ahydrogen and lower alkyl radicals, R1

represents a,member of the class consisting of hydrogen and CH3, R2 represents a member of the class consisting of hydrogen, chlorine, bro- --mine, iodine and lower alkyl radicals, Y represents a saturated divalent hydrocarbon radical of 2 to dear-bon atoms, R7 and Rs represent members of the class consisting of lower alkyl radicals-independently bonded to the N and lower alkylene radicals cyclically bonded to the N to form a heterocyclic ring system.

3. Compounds of the class consisting of a free --base and its acid addition salts, said free base having the formula,

ICHa

CH CHS Compoundsof the class consisting of a free baseeandlits. acid-addition salts, said free base having the formula,

17 5. Compounds of the class consisting of a free base and its acid addition salts, said free base having the formula,

N-OHa o omcmcmN CH2 0 Ha CH2 CH2 6. A compound of the formula,

0OHzCHzl T Hr*-CH2 8. A compound of the formula,

CHE' --CH2 CHzOHa Hc-CH2 9. Process which comprises treating the hydrochloride salt of a thiophenic acyl chloride of the formula,

with an amino alcohol of the formula NYOH and isolating the thiophenic ester so formed, said ester having the formula and Rs represent members of the class consisting of hydrogen and lower alkyl radicals, Y represents a saturated divalent hydrocarbon radical of 2 to 6 carbon atoms, R7 and Rs represent members of the class consisting of lower alkyl radicals independently bonded to the N and lower alkylene radicals cyclically bonded to the N to form a saturated heterocyclic ring system.

10. Process which comprises treating the hydrochloride salt of a thiophenic acylchloride of the formula,

with an amino alcohol of the formula,

.\NY-OH V V and isolating the thiophenic ester so formed, said ester having the formula,

where It represents a member of the class consisting of hydrogen and lower alkyl radicals, R1 represents a member of the class consisting of hydrogen and CI-I3, R2 represents a member of the class hydrogen, chlorine, bromine, iodine and lower alkyl radicals, Y represents a saturated divalent hydrocarbon radical of 2 to 6 carbon atoms, R1 and Rs represent members of the class consisting of lower alkyl radicals independently bonded to the N and lower alkylene radicals cyclically bonded to the N to form a saturated heterocyclic ring system.

11. Process which comprises treating the hydrochloride salt of a thiophenic acyl chloride of the formula,

CH2-CH1 IL o S 0-0 NCHa.HCl

o1 (IJH2 Hz CH CH2 l SF CHzCHs N-CHs OCHzCHzN CHaOHz 12 Process which comprises treating the lay 19 20 drochloride salt of a thiophenic acyl chloride of drochloride salt of a thiophenic acyl chloride of the formula, the formula,

CH2 CH2 CH7-CH2 o \i ii a i I a o NCHs.HC1 \S -o NCHa.HCl

! 01 l 01 CHr-CH2 H2-CH2 with an amino alcohol of the formula, with an amino alcohol of the formula,

CH2 NOH2CH2OH /NCHzCH2CH2OH CHa-CH2 01130112 and isolating the thiophenic ester so formed, said and. isolating the thiophenic ester so formed, said ester having the formula ester havingthe formula,

CHz CH2 oH2---c111 T IL 0 i il 0 \S/ C\ CH2CH: N-CHa S/C-C CHrCHaN CH O-CHQOHQI T CH2 ooiizom'omNv a CH2CH2 012mm oH2 CH2 CHz---CH1 13. Process which comprises treating thehy- FREDERICK F; BLICKE. 

